Despite the widespread use of combination antiretroviral therapy (cART), approximately half of individuals with HIV-infection are affected by HIV-associated neurocognitive disorders (HAND). Individuals with even the mildest form of HAND, asymptomatic neurocognitive impairment (ANI), are at increased risk of antiretroviral non-adherence, virologic failure, unemployment and mortality. There has been increasing pressure to identify neural targets for interventional behavioral and medical therapies, especially among persons at risk of progression to symptomatic HAND. Early interventions (prior to potentially additive neural damage) are likely to be more effective and have a better chance to preserve and improve cognitive function. Despite this significant public health need, finding a biomarker that can accurately assess current neurocognitive disease stage and reliably predict future HAND progression remains a major challenge. Here we hypothesize that, in HIV+ individuals without symptomatic HAND, subtle neuronal dysfunction due to synaptodendritic injury, not currently assessed clinically, is present and can be detected and quantitated using the novel functional magnetic resonance imaging (fMRI) techniques we recently developed and validated. In this 5-year cross- sectional and longitudinal study, we aim to further validate and improve these fMRI biomarkers (based on two novel techniques) with a larger sample size, both cross-sectionally and longitudinally (primary goal). We will study a total of 160 subjects over five years. These will include 100 neurocognitively normal/ANI HIV-positive, virally suppressed adults on cART, and 60 matched HIV negative controls. HIV+ individuals will have a 24- month follow-up visit. Based on a recent study (Grant et al., Neurology, 2014), we expect about 20 HIV+ participants will transition from neurocognitively normal or ANI to symptomatic HAND over the 2-year period. This longitudinal data will provide us an opportunity to follow the trajectories of transition with novel fMRI techniques and to identify potential markers of risk for progression to symptomatic HAND (secondary goal). This project has three specific aims: Aim 1: To test the hypothesis that HIV impairs neurocognitive function by decreasing neural specificity in key brain regions and to identify brain regions that are most vulnerable to HIV- disease (i.e., those with the greatest reductions in neural specificity). Aim 2: To test the hypothesis that HAND leads to accelerated/premature aging of the brain, by calculating a functional age of the HIV-infected brain with multivariate pattern analysis (MVPA) of fMRI activations relative to HIV-uninfected controls, and to quantify accelerated aging in HIV at the whole-brain level as a single diagnostic number, Hage (Hage = functional age minus chronological age) that can be linked to HAND progression and future risk, with a strong potential to serve as a biomarker of HAND in clinical settings. Aim 3: To evaluate the neural bases of reduced executive function due to HIV infection, one of the most common and key deficits that underlies a broad range of neurocognitive impairments associated with HAND. The success of this proposed project is expected to provide clinicians and researchers with a validated set of tools/biomarkers to quantitatively assess early pathological changes and to predict future HAND progression, with a strong potential to guide and evaluate interventions that might slow down or prevent progression to symptomatic HAND.